Lactoferrin (LF) is a metal binding glycoprotein of Mr 77,000 found in milk, tears, saliva, bronchial, intestinal, and other secretions. LF is also present in the secondary granules of neutrophils. Lactoferrin plays an important role in numerous inflammatory and immune response functions such as regulation of monocyte colony stimulating factor synthesis, activation of natural killer cell activity, inhibition of metastasis, and maturation of T-cells. Lactoferrin also inhibits myelopoiesis, binds to members of the low density lipoprotein receptor family, and blocks the clearance of lipoprotein chylomicron remnant particles (2, 32, 33, 34). It also appears to play a role in inhibiting the production or release of prostaglandin E2, interleukins, and tumor necrosis factor by mononuclear cells (35, 36, 37).
Human lactoferrin (hLF) is also a major component of the non-specific defense of mucosal surfaces and neutrophils and is active against a variety of pathogens (reviewed in 1,2). This protein displays antimicrobial properties against Gram-positive and Gram-negative bacteria by limiting the availability of environmental iron (3). However, since iron-saturated hLF is also able to kill certain bacteria (4), mechanisms other than iron-depletion apparently are involved in the antibacterial activity of lactoferrin.
The amino acid sequence of LF has been determined by protein-sequencing and sequencing of cDNA clones. Human LF (hLF) consists of a polypeptide chain of 692 amino acids and contains two N-terminal cationic domains, i.e., RRRR (residues 2–5 of SEQ ID NO:1) and RK VR (residues 28–31 of SEQ ID NO:1), whereas bovine lactoferrin (bLF) has only one cationic domain (residues 17–42 (8,9)). The LF polypeptide is folded into two globular lobes, each of which contains an iron-binding cleft. The high affinity of LF for iron confers to the protein certain antibacterial properties and, in addition, may play a role in the absorption of dietary iron by the small intestine.
It has been reported that peptides of bLF origin (9) as well as synthetic peptides that include the second cationic domain of hLF (12) show antibacterial activity resulting from depolarization of the membrane, increased membrane permeability and metabolic injury. There is considerable controversy over whether hLF binds to bacterial products, such as endotoxin and glycosaminoglycans, through its first (13–15) or second (16,17) cationic domain. One group of researchers has concluded that a loop region consisting of amino acid residues 20 to 37 of hLF is responsible for the antibacterial effect of hLF, whereas residues 1 to 17 at the N-terminal region are not essential (5).